Vitamin D analogues

Abstract

The invention relates to compounds of formula I in which formula X is hydrogen or hydroxy; R 1 and R 2 stand for hydrogen or a C 1 -C 6 hydrocarbyl radical; or taken together with the carbon atom bearing the group X, can form a C 3 -C 8 carbocyclic ring; R 3 stands for hydrogen or a C 1 -C 10 hydrocarbyl radical or for YR 4 , in which Y stands for the radicals --CO--, --CO--O--, --CO--S--, --CS--, --CS--O--, --CS--S--, --SO-- or SO 2 --, and R 4 stands for hydrogen or a C 1 -C 10 hydrocarbyl radical; Q is a single bond or a C 1 -C 8 hydrocarbylene diradical. R 1 ,R 2 ,R 3 and/or Q may be optionally substituted with one or more deuterium or fluorine atoms. The compounds show an antiinflammatory and immunomodulating effect as well as stong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells.

What we claim is: 
     
       1. A compound of the formula I ##STR14## in which formula X is hydrogen or hydroxy; R 1  and R 2  which may be the same or different, stand for hydrogen or a C 1  -C 6  hydrocarbyl radical; or R 1  and R 2  taken together with the carbon atom (starred in formula I) bearing the group X, can form a C 3  -C 8  carbocyclic ring; R 3  stands for hydrogen or a C 1  -C 10  hydrocarbyl radical or for YR 4  in which Y stands for the radicals --CO--, --CO--O--, --CO--S--, --CS--, --CS--O--, --CS--S--, --SO-- or --SO 2  --, and R 4  stands for hydrogen or a C 1  -C 10  hydrocarbyl radical; Q is a single bond or a C 1  -C 8  hydrocarbylene diradical; R 1 , R 2 , R 3  and/or Q may be optionally substituted with one or more deuterium or fluorine atoms. 
     
     
       2. A diastereoisomer of a compound according to claim 1, in pure form; or a mixture of diastereoisomers of a compound according to claim 1. 
     
     
       3. A compound according to claim 1 which is 1(S),3(R)-Dihydroxy-20(R)-(1,5-dihydroxy-5-ethyl-2-heptyn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A,   1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-5-hydroxy-1-methoxy-2-heptyn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A,   1(S),3(R)-Dihydroxy-20(R)-(1-ethoxy-5-ethyl-5-hydroxy-2-heptyn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A,   1(S),3(R)-Dihydroxy-20(R)-(1-methoxy-4-hydroxy-4-ethyl-2-hexyn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A, or   1(S),3(R)-Dihydroxy-20(R)-(1-ethoxy-4-hydroxy-4-ethyl-2-hexyn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A.   
     
     
       4. A method for producing a compound of formula I: ##STR15## in which formula X is hydrogen or hydroxy; R 1  and R 2  which may be the same or different, stand for hydrogen or a C 1  -C 6  hydrocarbyl radical; or R 1  and R 2  taken together with the carbon atom (starred in formula I) bearing the group X, can form a C 3  -C 8  carbocyclic ring; R 3  stands for hydrogen or a C 1  -C 10  hydrocarbyl radical or for YR 4  in which Y stands for the radicals --CO--, --CO--O--, --CO--S, --CS--, --CS--O--, --CS--S--, --SO-- or --S02--, and R 4  stands for hydrogen or a C 1  -C 10  hydrocarbyl radical; Q is a single bond or a C 1  -C 8  hydrocarbylene diradical; R 1 , R 2 , R 3  and/or Q may be optionally substituted with one or more deuterium or fluorine atoms, in which a) 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-formyl-9,10-seco-pregna-5(E),7(E),10(19)-triene is reacted with the anion R - , derived from the side chain building block, RH, of formula V   V: RH, R being ##STR16##  which X 1  is H, OH or OR 5 , R 5  being an alcohol protective group, and R 1 , R 2  and Q have the above meanings with a suitable base, to form a mixture of two C-22-epimers IIA and IIB, in which R 3  stands for H, and R have the above meaning ##STR17##  which epimers are separated; b) a compound of formula IIA or IIB of step a), where R 3  =H, is optionally alkylated to the corresponding compound IIA or IIB, in which R 3  is C 1  -C 10  hydrocarbyl or optionally acylated to the corresponding compound IIA or IIB, where R 3  =YR 4 , Y and R 4  having the above meanings;   c) a compound of formula IIA or IIB of step a) or step b) is isomerized to the corresponding compound IIIA or IIIB by means of UV-light in the presence of a triplet sensitizer ##STR18##  in which R and R 3  have the above meanings; d) a compound of formula IlIA or IIIB is deprotected to the corresponding compound of the general formula I.   
     
     
       5. A method according to claim 4 in which steps b) and c) are performed in the reverse order. 
     
     
       6. A pharmaceutical composition containing an effective amount of one or more of the compounds of claim 1, together with pharmaceutically acceptable, non-toxic carriers. 
     
     
       7. A pharmaceutical composition according to claim 6 in dosage unit form. 
     
     
       8. A dosage unit according to claim 7 containing from 0.1 ppm to 0.1% by weight of the dosage unit of a compound of formula I.